As metastases are the major cause of cancer deaths, there is an urgent need for the development of cancer therapies aimed at interfering with tumor progression, which results in the metastatic dissemination of a tumor and the acquisition of resistance to many of the currently available therapeutics. The identification of molecules that control tumor progression to be used as targets for anti-tumor strategies is an essential step in advancing novel interventions aimed at preventing and/or treating metastatic disease. The epithelial-mesenchymal transition (EMT) has now been recognized as a mechanism utilized by carcinoma cells to metastasize; in addition to gaining motility and invasiveness, tumor cells that undergo EMT are also able to acquire increased resistance to many traditional cancer treatment modalities, including chemotherapy and radiation, and some small-molecule targeted therapies. Our laboratory has recently identified the transcription factor Brachyury as a driver of EMT in human carcinomas. High levels of Brachyury expression result in the acquisition of tumor cell motility and invasiveness in vitro and facilitate metastatic dissemination in vivo in animal models. In additional studies we have demonstrated that Brachyury also promotes tumor resistance to chemotherapy and radiation as well as to the targeted inhibition of the epidermal growth factor receptor (EGFR) in lung carcinoma cells. Due to its potentially relevant role in cancer metastasis, we have then studied the pattern of expression of Brachyury across a range of human tissues. Our results demonstrated that Brachyury is preferentially expressed in human carcinomas, including lung, breast, colon and ovarian, while being absent in the majority of normal tissues evaluated, with the exception of some levels detected in normal testis and some thyroid tissues. In order to understand whether an immunotherapeutic approach could be employed to target Brachyury-positive tumors, a 9-mer CD8 T-cell epitope of Brachyury was identified which was used in vitro to expand Brachyury-specific T cells from the peripheral blood of cancer patients and some healthy donors. The expanded Brachyury-specific T cells were successfully used in vitro to lyse tumor cells of lung, breast, colon and prostate cancer origin that naturally express the brachyury protein. These results thus formed the rationale for the development of cancer vaccine platforms to target Brachyury, one of which is currently ongoing Phase I clinical evaluation. More recently, we have investigated potential inducers of Brachyury expression in tumor cells. The chemokine IL-8 was identified as a major factor that induces EMT and Brachyury in human carcinoma cells, thus providing a potentially new strategy to revert the mesenchymal, metastastic and drug resistant phenotype of a tumor by modulating IL-8 signaling in the tumor microenvironment.